Concise and Scalable Radiosynthesis of (+)-[18F]MDL100907 as a Serotonin 5-HT2A Receptor Antagonist for PET

Abstract

5-Hydroxytryptamine (5-HT_2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [¹⁸F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [¹⁸F]MDL100907. Here, we report a highly efficient, scalable, and expedient synthesis for [¹⁸F]MDL100907. The radiofluorination was performed on a ¹⁸F-labeling boron pinacol ester precursor, which is synthesized using the Liebeskind-Srogl cross-coupling reaction as a key step. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of the [¹⁸F]MDL100907 radioligand in excellent decay-corrected RCY of 32 ± 10% (n = 7) within 60 min. We prepared [¹⁸F]MDL100907 in high molar activity (2.1 Ci/μmol) and compared it to [¹¹C]MDL100907 in the brain of a nonhuman primate.

Keywords: 5-HT2A; Liebeskind−Srogl reaction; copper catalysis; radiofluorination.

Figure 1

PET-based radioligands.

Scheme 1. Previous and Present Approaches

Scheme 2. Synthesis of (±) MDL100907 and Iodo-Analogue

Scheme 3. Synthesis of Pinacol Boron Ester Precursor

Scheme 4. Cu-Mediated Late-Stage Radiolabeling^,

Reaction conditions: The reaction was carried out with 15 (1.5 mmol), Cu(OTf)₂(py)₄ (3.1 mmol), fluoride source, and TEABC (1.5 mg) in DMA/nBuOH (300/100 μL). Decay-corrected radiochemical yields of products isolated after HPLC purification.

Figure 2

5-HT_2A distribution microPET brain uptake.